Mild traumatic brain injury (mTBI), primarily caused by blast exposures, has been called the signature injury of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Many Veterans are at increased risk for persisting mTBI-related cognitive difficulties due to repeated blast exposures over the course of one or more deployment(s) and limited time for recovery between injuries. Despite the high number of OIF/OEF Veterans presenting to VA medical centers with persisting cognitive difficulties, our current understanding of the etiology of these difficulties, including the impact of repeated blast exposures on brain structure and functioning, is limited. Further, there continues to be significant debate regarding the contribution of comorbid conditions, such as posttraumatic stress disorder, to objective and subjective measures of cognitive functioning in this population. This study will address some of these gaps in the literature by evaluating the neural underpinnings of persisting cognitive difficulties in Veterans with a history of repeated blast-related mTBI. Specifically, our preliminary research involving OIF/OEF Veterans with a history of blast-related mTBI has found evidence of both reduced working memory on neuropsychological measures and cerebellar abnormalities that are visible on neuroimaging. A large scale brain system that includes both cortical and cerebellar components is involved in verbal working memory, and this Career Development Award will investigate the functional and structural integrity of that system. Two complementary neuroimaging methodologies (resting state functional connectivity fMRI and diffusion tensor imaging and) will be used to investigate the functional connectivity of the cerebral components of this network with the cerebellar components, and the integrity of the white matter tracts that physically mediate this connectivity. Further, the relationship between the neuroimaging findings and both neuropsychological assessment of working memory ability and self-reported cognitive difficulties will be evaluated. Veterans with a history of repeated blast-related mTBI with and without PTSD will be compared to OIF/OEF Veterans with no history of blast-related mTBI. This research will provide critical information that will improve our understanding of blast-related mTBI, the neural underpinnings of working memory difficulties in this population, and ultimately the selection of the most appropriate treatment interventions. PUBLIC HEALTH RELEVANCE: Blast-related mild traumatic brain injury (mTBI) is considered the signature injury of the conflicts in Iraq and Afghanistan (Operation Iraqi Freedom and Operation Enduring Freedom, respectively), but the effect of these injuries on brain structure and function is not yet understood. This study will address some of those gaps by investigating the neural underpinnings of working memory deficits in this population. The relationship between neuroimaging findings, neuropsychological functioning, and cognitive symptoms reported by OIF/OEF Veterans will be evaluated. This study has the potential to significantly improve our understanding of the effects of blast-related mTBI on brain functioning as well as our ability to identify and treat this condition.